Gemcitabine of formula (A), a medicament for treating non-small cell lung cancer (NSCLC), is a synthetic nucleoside analogue having a cytosine nucleobase stereochemically oriented upward to the β-direction at C-1 of the ribofuranose backbone.

Gemcitabine may be conventionally prepared from a lactol compound as shown in Reaction Scheme 1 via an activated ribofuranose intermediate having a reactive leaving group:

wherein, P1 is a hydroxy protecting group, and L is a leaving group.
Specifically, gemcitabine may be prepared by 1a) introducing a reactive leaving group (L) into C-1 of the ribofuranose ring of a lactol compound (B) to obtain an activated ribofuranose intermediate (C), and 1b) glycosylating the compound of formula (C) with cytosine to form an N-glycosidic bond.
In Reaction Scheme 1, glycosylation step 1b) undergoes via a bimolecular (SN2) mechanism of nucleophilic substitution, and thus, it is important in the preparation of gemcitabine to obtain a high purity α-anomer of the compound (C) having the leaving group (L) oriented down. Accordingly, many attempts have been made to develop a process for stereoselectively introducing a leaving group (L) into C-1 of the ribofuranose ring of the lactol compound (B).
For example, U.S. Pat. Nos. 4,526,988 and 5,453,499 disclose an activated ribofuranose intermediate such as 1-α-halo-ribofuranose having a halo leaving group introduced at C-1 of the ribofuranose ring. Specifically, U.S. Pat. No. 4,526,988 describes a method for preparing a 1-α-halo-ribofuranose derivative of formula (F) by 2a) reacting the 1-hydroxy group of a lactol compound of formula (D) with an acetyl source such as acetic anhydride to obtain a 1-acetate derivative of formula (E), and 2b) reacting the 1-acetate derivative of formula (E) with gaseous HBr or HCl to obtain a 1-halo ribofuranose, as shown in Reaction Scheme 2:

wherein, R′ is a hydroxy protecting group, Ac is acetyl, and X is Br or Cl.
However, this process gives a low yield of the desired α-halo anomer due to its low stereoselectivity.
U.S. Pat. No. 5,453,499 discloses a process for preparing an α-enriched 1-halo ribofuranose of formula (H) having an α:β ratio of 9:1 to 10:1 by reacting a β-sulfonate compound of formula (G) with a halide source in an inert solvent, as shown in Reaction Scheme 3:

wherein, P″ is a hydroxy protecting group such as benzoyl, R″ is sulfonate, and Y is halogen.
However, the 1-sulfonate compound of formula (G) used as a starting material in this process, prepared via a lactol compound by the method described in U.S. Pat. No. 5,401,861, has an α:β ratio of about 1:4, and therefore, the overall stereoselectivity (α:β) ratio for the 1-halo anomer is only about 3:1.
Further, the prior 1-α-halo-furanoses having the 3- and 5-hydroxy groups protected, e.g., by benzoyl groups, exist in an oily state which is more difficult to handle and store than a solid form, besides the fact that an uneconomical column chromatography process is required for its isolation from a mixture of α- and β-anomers. Therefore, there has been a need to develop an improved process for preparing gemcitabine using an α-halo-furanose as an intermediate.